Developing an in-depth understanding of the factors that regulate the induction, quality, and longevity of anti- viral T cell responses is essential for devising rational strategies to combat viral infections. A hallmark of robust anti-viral immunity is the elaboration of potent CD4 and CD8 T cell responses which act cooperatively to bring about control of the infection. The consequences of ineffective responses can be catastrophic, resulting in viral persistence or the loss of long-lived immunological memory. Nevertheless, the signals which drive the development of the most robust polyfunctional effector responses and dictate the emergence of memory T cells are not fully understood. The purpose of this proposal is to capitalize on compelling preliminary findings which indicate that IL-21 plays a vital role in anti-viral immunity. Our initial studies clearly show that without sufficient levels of IL-21 the generation of polyfunctional effector CD8 T cells is compromised, and quite strikingly T cell exhaustion is exacerbated during chronic infections. Significantly, many of the phenotypic and functional impairments in anti-viral CDS T cells which manifest in the absence of IL-21 resemble the defects observed in CD4 T cell deficient hosts. A principal producer of IL-21 are CD4 follicular helper cells (Tfh) which function to help antibody responses, therefore Tfh derived IL-21 may be the critical factor that helps CD8 T cell responses. It is, however, unclear whether IL-21 is acting directly or indirectly on anti-viral CD8 T cells to promote their functionality, how T cell heterogeneity is shaped by IL-21, whether Tfh are the essential cellular sources of IL-21, and whether IL-21 based treatments have therapeutic benefits on viral control both during acute and chronic infection. We therefore propose the following specific aims: 1). Determine the direct effects of IL-21 on polyfunctional anti-viral CDS T cells. 2). Elucidate the role of CD4 T cell-derived IL-21 in promoting anti-viral immunity. 3). Define the significance of IL-21-producing CD4 T cells during viral infections of humans 4). Determine the therapeutic effects of IL-21 on anti-viral immunity and control.